Hyperglycemia Induced Cerebral Hematoma Expansion is Mediated by Plasma Kallikrein

Hyperglycemia is associated with increased hematoma expansion and worse clinical outcomes following intracerebral hemorrhage. We demonstrate that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is increased in diabetic rats and mice, and this response is ameliorated by plasma kallikrein (PK) inhibition and deficiency, respectively. Both diabetes and hyperglycemia induced in nondiabetic rats increase hematoma expansion following intracerebral injection of purified PK, a response not observed with bradykinin, plasmin, or tissue plasminogen activator. This response is rapid, prevented by co-injection of the glycoprotein VI (GPVI) agonist convulxin, and mimicked by GPVI inhibition or deficiency. We show that PK binding to collagen and PK-mediated inhibition of collagen-induced platelet aggregation is enhanced by hyperglycemia. Hyperosmotic mannitol also increases hematoma expansion induced by blood and PK, and increases PK-mediated inhibition of platelet aggregation. These findings suggest that hyperglycemia increases cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis.